Substituted pyrazoline compounds, their preparation and use as medicaments

ABSTRACT

The present invention relates to substituted pyrazoline compounds, methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans and animals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/169,155, filed Jun. 27, 2005, which is a continuation-in-part of U.S.application Ser. No. 10/804,534, filed Mar. 19, 2004, now abandoned,which claims the benefit of priority of Spanish application No. 200400378, filed Feb. 17, 2004. The above-referenced applications are herebyincorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

The present invention relates to substituted pyrazoline compoundsmethods for their preparation, medicaments comprising these compounds aswell as their use for the preparation of a medicament for the treatmentof humans and animals.

Cannabinoids are compounds, which are derived from the cannabis salivaplant which is commonly known as marijuana. The most active chemicalcompound of the naturally occurring cannabinoids is tetrahydrocannabinol(THC), particularly Δ⁹ -THC.

These naturally occurring cannabinoids as well as their syntheticanalogues promote their physiological effects via binding to specificG-coupled receptors, the so-called, cannabinoid-receptors.

At present, two distinct types of receptors that bind both the naturallyoccurring and synthetic cannabinoids have been identified and cloned.These receptors, which are designated CB₁ and CB₂ are involved in avariety of physiological or pathophysiological processes in humans andanimals, e.g. processes related to the central nervous system, immunesystem. cardiovascular system, endocrinous system, respiratory system,the gastrointestinal tract or to reproduction, as described for example,in Hollister, Pharm. Rev. 38, 1986, 1-20; Reny and Singha, Prog. Drug.Res. 36, 71-114, 1991; Consroe and Sandyk, in Marijuana/Cannabinoids,Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds., CRCPress, 1992.

Therefore, compounds which have a high binding affinity for thesecannabinoid receptors and which are suitable for modulating thesereceptors are useful in the prevention and/or treatment ofcannabinoid-receptor related disorders.

In particular, the CB₁-Receptor is involved in many differentfood-intake related disorders such as bulimia or obesity, includingobesity associated with type II diabetes (non-insulin-dependentdiabetes) and thus, compounds suitable for regulating this receptor maybe used in the prophylaxis and/or treatment of these disorders.

Thus, it was an object of the present invention to provide novelcompounds for use as active substances in medicaments, which aresuitable for the modulation of Cannabinoid receptors, particularlyCannabinoid 1 (CB₁) receptors.

Said object was achieved by providing the substituted pyrazolinecompounds of general formula I given below, their stereoisomers,corresponding salts and corresponding solvates thereof.

It has been found that these compounds have a high affinity forcannabinoid receptors, particularly for the CB₁-receptor and that theyact as antagonists on these receptors. They are therefore suitable forthe prophylaxis and/or treatment of various disorders related to thecentral nervous system, the immune system, the cardiovascular system,the endocrinous system, the respiratory system, the gastrointestinaltract or reproduction in humans and/or animals, preferably humansincluding infants, children and grown-ups.

Thus, in one of its aspects the present invention relates to substitutedpyrazoline compounds of general formula

wherein

R¹ represents an optionally at least mono-substituted phenyl group,

R² represents an optionally at least mono-substituted phenyl group,

R³ represents a saturated or unsaturated, optionally at leastmono-substituted, optionally at least one heteroatom as ring membercontaining cycloaliphatic group, which may be condensed with anoptionally at least mono-substituted mono- or polycyclic ring system, orR³ represents an optionally at least mono-substituted aryl, orheteroaryl group, which may be condensed with an optionally at leastmono-substituted mono- or polycyclic ring system, or R³ represents an—NR⁴R⁵-moiety,

R⁴ and R⁵, identical or different, represent a hydrogen atom, anunbranched or branched, saturated or unsaturated, optionally at leastmono-substituted aliphatic radical, a saturated or unsaturated,optionally at least mono-substituted, optionally at least one heteroatomas ring member containing cycloaliphatic group, which may be condensedwith an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono-substituted aryl or heteroarylgroup, which may be condensed with an optionally at leastmono-substituted mono- or polycyclic ring system and/or bonded via alinear or branched alkylene group, an —SO₂—R⁶-moiety, or an—NR⁷R⁸-moiety,

R⁶ represents a linear or branched, saturated or unsaturated, optionallyat least mono-substituted aliphatic group, a saturated or unsaturated,optionally at least mono-substituted, optionally at least one heteroatomas ring member containing cycloaliphatic group, which may be condensedwith a mono- or polycyclic ring-system, or an optionally at leastmono-substituted aryl or heteroaryl group, which may be condensed with amono- or polycyclic ring system and/or bonded via a linear or branchedalkylene group,

R⁷ and R⁸, identical or different, represent a hydrogen atom, anunbranched or branched, saturated or unsaturated, optionally at leastmono-substituted aliphatic radical, a saturated or unsaturated,optionally at least mono-substituted, optionally at least one heteroatomas ring member containing cycloaliphatic group, which may be condensedwith an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono-substituted aryl or heteroarylgroup, which may be condensed with an optionally at leastmono-substituted mono- or polycyclic ring system and/or bonded via alinear or branched alkylene group,

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding N-oxide thereof, or a correspondingsalt thereof, or a corresponding solvate thereof.

Particularly preferably the following provisos (disclaimers) apply forthe pyrazoline compounds of general formula I given above:

that R⁴ and R⁵ do not both represent a hydrogen atom, and

that if one of the residues R⁴ and R⁵ represents a hydrogen atom or analkyl group, which is optionally at least mono-substituted with analkoxy group, an alkoxyalkoxy group, a halogen atom or a phenyl group,the other one of these residues R⁴ and R⁵ does not represent apyrid-2-yl group, which is optionally mono-substituted in the5-position, a pyrid-5-yl group, which is optionally mono-substituted inthe 2-position, a pyrimid-5-yl group, which is optionallymono-substituted in the 2-position, a pyridaz-3-yl group, which isoptionally mono-substituted in the 6-position, a pyrazin-5-yl group,which is optionally mono-substituted in the 2-position, a thien-2-ylgroup, which is optionally mono-substituted in the 5 position, athien-2-yl group, which is optionally at least mono-substituted in the4-position, a benzyl group, which is optionally mono-substituted in the4-position of the ring, a phenethyl group, which is optionallymono-substituted in the 4-position of the ring, an optionally mono-, di-or tri-substituted phenyl group, a di-substituted phenyl group, whereinthe two substituents together form an —OCH₂O—, —OCH₂CH₂O— or —CH₂CH₂O—chain, which is optionally substituted with one or more halogen atoms orone or two methyl groups, an —NH-phenyl-moiety, wherein the phenyl groupmay be mono-substituted in the 4-position, and

that if one of the residues R⁴ and R⁵ represents an alkynyl group, theother one of these residues R⁴ and R⁵ does not represent a phenyl group,which is optionally substituted in the 4-position, and

that if one of the residues R⁴ and R⁵ represents a hydrogen atom or alinear or branched, saturated or unsaturated, unsubstituted orsubstituted aliphatic radical, the other one of these residues R⁴ and R⁵does not represent an unsubstituted or substituted thiazole group or anunsubstituted or substituted [1,3,4]thiadiazole group.

A mono- or polycyclic ring-system according to the present inventionmeans a mono- or polycyclic hydrocarbon ring-system that may besaturated, unsaturated or aromatic. If the ring system is polycyclic,each of its different rings may show a different degree of saturation,i.e. it may be saturated, unsaturated or aromatic. Optionally each ofthe rings of the mono- or polycyclic ring system may contain one or moreheteroatoms as ring members, which may be identical or different andwhich can preferably be selected from the group consisting of N, O, Sand P, more preferably be selected from the group consisting of N, O andS. Preferably the polycyclic ring-system may comprise two rings that arecondensed. The rings of the mono- or polycyclic ring-system arepreferably 5- or 6-membered. The term “condensed” according to thepresent invention means that a ring or ring-system is attached toanother ring or ring-system, whereby the terms “annulated” or“annelated” are also used by those skilled in the art to designate thiskind of attachment.

If one or more of the residues R³-R⁸ represents or comprises a saturatedor unsaturated, optionally at least one heteroatom as ring membercontaining cycloaliphatic group, which is substituted by one or moresubstituents, unless defined otherwise, each of the substituents may beindependently selected from the group consisting of hydroxy, fluorine,chlorine, bromine, branched or unbranched C₁₋₈-alkoxy, branched orunbranched C₁₋₆alkyl, unbranched C₁₋₄-perfluoroalkoxy, branched orunbranched C₁₋₄-perfluoroalkyl, oxo, amino, carboxy, amido, cyano,nitro, —SO₂NH₂, —CO—C₁₋₄-alkyl, —SO—C₁₋₄alkyl, —SO₂—C₁₋₄-alkyl,—NH—SO₂—C₁₋₄-alkyl, wherein the C₁₋₄-alkyl may in each case be branchedor unbranched, and a phenyl group, more preferably be selected from thegroup consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy,oxo, CF₃ and a phenyl group.

If one or more of the residues R³-R⁸ represents or comprises acycloaliphatic group, which contains one or more heteroatoms as ringmembers, unless defined otherwise, each of these heteroatoms maypreferably be selected from the group consisting of of N, O and S.

Suitable saturated or unsaturated, optionally at least one heteroatom asring member containing, optionally at least mono-substitutedcycloaliphatic groups may preferably be selected from the groupconsisting of Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl,Cycloheptyl, Cyclooctyl, Cyclopentenyl, Cyclohexenyl, Cycloheptenyl,Cyclooctenyl, Pyrrolidinyl, Piperidinyl, Piperazinyl, homo-Piperazinyland Morpholinyl.

If one or more of the residues R³-R⁸ comprises a mono- or polycyclicring system which is substituted by one or more substituents, unlessdefined otherwise, each of the substituents may be independentlyselected from the group consisting of hydroxy, fluorine, chlorine,bromine, branched or unbranched C₁₋₆-alkoxy, branched or unbranchedC₁₋₆-alkyl, branched or unbranched C₁₋₄-perfluoroalkoxy, branched orunbranched C₁₋₄-perfluoroalkyl, amino, carboxy, oxo, amido, cyano,nitro, —SO₂NH₂, —CO—C₁₋₄-alkyl, —SO—C₁₋₄-alkyl, —SO₂—C₁₋₄-alkyl,—NH—SO₂—C₁₋₄-alkyl wherein the C₁₋₄-alkyl may in each case be branchedor unbranched, and a phenyl group, more preferably be selected from thegroup consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy,CF₃, oxo and a phenyl group.

If one or more of the residues R¹-R⁸ represents or comprises an arylgroup, including a phenyl group, which is substituted by one or moresubstituents, unless defined otherwise, each of the substituents may beindependently selected from the group consisting of a halogen atom, alinear or branched C₁₋₆-alkyl group, a linear or branched C₁₋₆ alcoxygroup, a formyl group, a hydroxy group, a trifluoromethyl group, atrifluoromethoxy group, a —CO—C₁₋₆-alkyl group, a cyano group, a nitrogroup, a carboxy group, a —CO—O—C₁₋₆-alkyl group, a —CO—NR^(A)R^(B)—moiety, a —CO—NH—NR^(C)R^(D)-moiety, an —SH, an —S—C₁₋₆-alkyl group, an—SO—C₁₋₆-alkyl group, an —SO₂—C₁₋₆-alkyl group, a—C₁₋₆-alkylene-S—C₁₋₆-alkyl group, a —C₁₋₆-alkylene-SO—C₁₋₆-alkyl group,a —C₁₋₆-alkylene-SO₂—C₁₋₆-alkyl group, an —NH₂-moiety, an NHR′-moiety oran NR′R″-moiety, wherein R′ and R″ independently represent a linear orbranched C₁₋₆-alkyl group, a C₁₋₆-alkyl group substituted by one or morehydroxy groups and a —C₁₋₆-alkylene-NR^(E)R^(F) group,

whereby R^(A), R^(B), identical or different, represent hydrogen or aC₁₋₆-alkyl group, or R^(A) and R^(B) together with the bridging nitrogenatom form a saturated mono- or bicyclic, 3-10membered heterocyclic ringsystem, which may be at least mono-substituted by one or more, identicalor different, C₁₋₆ alkyl groups and/or which may contain at least onefurther heteroatom selected from the group consisting of nitrogen,oxygen and sulphur as a ring member,

R^(C), R^(D), identical or different, represent a hydrogen atom, aC₁₋₆-alkyl group, a —CO—O—C₁₋₆-alkyl group, a C₃₋₈-cycloalkyl group, aC₁₋₆-alkylene-C₃₋₈-cycloalkyl group, C₁₋₆-alkylene-O—C₁₋₆-alkyl group ora C₁₋₆-alkyl group substituted with one or more hydroxy groups, orR^(C), R^(D) together with the bridging nitrogen atom form a saturated,mono- or bicyclic, 3-10 membered heterocyclic ring system, which may beat least mono-substituted by one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl group, a —CO—C₁₋₆-alkylgroup, a —CO—O—C₁₋₆-alkyl group, a —CO—NH—C₁₋₆-alkyl group, a—CS—NH—C₁₋₆-alkyl group, an oxo group, a C₁₋₆-alkyl group substitutedwith one or more hydroxy groups, a C₁₋₆-alkylene-O—C₁₋₆-alkyl group anda —CO—NH₂ group and/or which may contain at least one further heteroatomselected from the group consisting of nitrogen, oxygen and sulphur as aring member, and

wherein R^(E), R^(F), identical or different, represent hydrogen or aC₁₋₆-alkyl group, or R^(E) and R^(F) together with the bridging nitrogenatom form a saturated, mono- or bicyclic, 3-10 membered heterocyclicring system, which may be at least mono-substituted by one or more,identical or different C₁₋₆ alkyl groups and/or which may contain atleast one further heteroatom selected from the group consisting ofnitrogen, oxygen and sulphur as a ring member.

Preferred aryl groups, which may optionally be at leastmono-substituted, are phenyl and naphthyl.

If one or more of the residues R³-R⁸ represents or comprises aheteroaryl group, which is substituted by one or more substituents,unless defined otherwise, each of the substituents may be independentlyselected from the group consisting of a halogen atom, a linear orbranched C₁₋₆-alkyl group, a linear or branched C₁₋₆ alcoxy group, aformyl group, a hydroxy group, a trifluoromethyl group, atrifluoromethoxy group, a —CO—C₁₋₆-alkyl group, a cyano group, a carboxygroup, a —CO—O—C₁₋₆-alkyl group, a —CO—NR^(A)R^(B)— moiety, a—CO—NH—NR^(C)R^(D)-moiety, an —S—C₁₋₆-alkyl group, an —SO—C₁₋₆-alkylgroup, an —SO₂—C₁₋₆-alkyl group, a —C₁₋₆-alkylene-S—C₁-alkyl group, a—C₁₋₆-alkylene-SO—C₁₋₆-alkyl group, a —C₁₋₆-alkylene-SO₂—C₁₋₆-alkylgroup, a C₁₋₆-alkyl group substituted by one or more hydroxy groups anda —C₁₋₆-alkylene-NR^(E)R^(F) group,

whereby R^(A), R^(B), identical or different, represent hydrogen or aC₁₋₆-alkyl group, or R^(A) and R^(B) together with the bridging nitrogenatom form a saturated, mono- or bicyclic, 3-10 membered heterocyclicring system, which may be at least mono-substituted by one or more,identical or different, C₁₋₆ alkyl groups and/or which may contain atleast one further heteroatom selected from the group consisting ofnitrogen, oxygen and sulphur as a ring member,

R^(C), R^(D), identical or different, represent a hydrogen atom, aC₁₋₆alkyl group, a —CO—O—C₁₋₆-alkyl group, a C₃₋₈-cycloalkyl group, aC₁₋₆-alkylene-C₃₋₈-cycloalkyl group, C₁₋₆-alkylene-O—C₁₋₆alkyl group ora C₁₋₆-alkyl group substituted with one or more hydroxy groups, orR^(C), R^(D) together with the bridging nitrogen atom form a saturated,mono- or bicyclic, 3-10 membered heterocyclic ring system, which may beat least mono-substituted by one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl group, a —CO—C₁₋₆-alkylgroup, a —CO—O—C₁₋₆-alkyl group, a —CO—NH—C₁₋₆-alkyl group, a—CS—NH—C₁₋₆-alkyl group, an oxo group, a C₁₋₆-alkyl group substitutedwith one or more hydroxy groups, a C₁₋₆-alkylene-C₁₋₆-alkyl group and a—CO—NH₂ group and/or which may contain at least one further heteroatomselected from the group consisting of nitrogen, oxygen and sulphur as aring member, and

wherein R^(E), R^(F), identical or different, represent hydrogen or aC₁₋₆-alkyl group, or R^(E) and R^(F) together with the bridging nitrogenatom form a saturated, mono- or bicyclic, 3-10 membered heterocyclicring system, which may be at least mono-substituted by one or more,identical or different C₁₋₆ alkyl groups and/or which may contain atleast one further heteroatom selected from the group consisting ofnitrogen, oxygen and sulphur as a ring member,

The heteroatoms, which are present as ring members in the heteroarylradical, may, unless defined otherwise, independently be selected fromthe group consisting of nitrogen, oxygen and sulphur.

Suitable heteroaryl groups, which may optionally be at leastmono-substituted, may preferably be selected from the group consistingof thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrimidinyl,pyrazinyl, indolyl, chinolinyl, isochinolinyl,benzo[1,2,5]-thiodiazolyl, benzo[b]thiophenyl, benzo[b]furanyl,imidazo[2,1-b]thiazolyl, triazolyl, and pyrazolyl, more preferably beselected from the group consisting of thienyl-,benzo[1,2,5]-thiodiazolyl, benzo[b]thiophenyl, imidazo[2,1-b]thiazolyl,triazolyl and pyrazolyl.

If one or more of the residues R⁴-R⁸ represents or comprises a linear orbranched, saturated or unsaturated aliphatic group, which is substitutedby one or more substituents, unless defined otherwise, each of thesubstituents may be independently selected from the group consisting ofhydroxy, fluorine, chlorine, bromine, branched or unbranchedC₁₋₄-alkoxy, branched or unbranched C₁₋₄-perfluoroalkoxy, branched orunbranched C₁₋₄-perfluoroalkyl, amino, carboxy, amido, cyano, nitro,—SO₂NH₂, —CO—C₁₋₄-alkyl, —SO—C₁₋₄-alkyl, —SO₂—C₁₋₄-alkyl,—NH—SO₂—C₁₋₄-alkyl, wherein the C₁₋₄-alkyl may in each case be branchedor unbranched, and a phenyl group, more preferably be selected from thegroup consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, CF₃ and aphenyl group.

Preferred linear or branched, saturated or unsaturated aliphatic groups,which may be substituted by one or more substituents, may preferably beselected from the group consisting of methyl, ethyl, n-propyl,isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl,n-heptyl, n-octyl, n-nonyl, n-decyl, vinyl, ethinyl, propenyl, propinyl,butenyl and butinyl.

If any of the residues R⁴-R⁸ represents or comprises a linear orbranched alkylene group, said alkylene group may preferably be selectedfrom the group consisting of -methylene-(CH₂)—, ethylene —(CH₂—CH₂)—,n-propylene —CH₂—CH₂—CH₂Y or iso-propylene —C(CH₃)₂)—.

Preferred are substituted pyrazoline compounds of general formula Igiven above, wherein

R¹ represents an optionally at least mono-substituted phenyl group,

R² represents an optionally at least mono-substituted phenyl group,

R³ represents a saturated or unsaturated, optionally at leastmono-substituted, optionally at least one heteroatom as ring membercontaining cycloaliphatic group, which may be condensed with anoptionally at least mono-substituted mono- or polycyclic ring system, orR³ represents an optionally at least mono-substituted aryl or heteroarylgroup, which may be condensed with an optionally at leastmono-substituted mono- or polycyclic ring system, or R³ represents an—NR⁴R⁵-moiety,

R⁴ and R₅, identical or different, represent a hydrogen atom, anunbranched or branched, saturated or unsaturated, optionally at leastmono-substituted aliphatic radical, a saturated or unsaturated,optionally at least mono-substituted, optionally at least one heteroatomas ring member containing cycloaliphatic group, which may be condensedwith an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono-substituted aryl or heteroarylgroup, which may be condensed with an optionally at leastmono-substituted mono- or polycyclic ring system and/or bonded via alinear or branched alkylene group, an —SO₂-R⁶— moiety, or an—NR⁷R⁸-moiety,

R⁶ represents a linear or branched, saturated or unsaturated, optionallyat least mono-substituted aliphatic group, a saturated or unsaturated,optionally at least mono-substituted, optionally at least one heteroatomas ring member containing cycloaliphatic group, which may be condensedwith a mono- or polycyclic ring-system, or an optionally at leastmono-substituted aryl or heteroaryl group, which may be condensed with amono- or polycyclic ring system and/or bonded via a linear or branchedalkylene group,

R⁷ and R⁸, identical or different, represent a hydrogen atom, anunbranched or branched, saturated or unsaturated, optionally at leastmono-substituted aliphatic radical, a saturated or unsaturated,optionally at least mono-substituted, optionally at least one heteroatomas ring member containing cycloaliphatic group, which may be condensedwith an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono-substituted aryl or heteroarylgroup, which may be condensed with an optionally at leastmono-substituted mono- or polycyclic ring system and/or bonded via alinear or branched alkylene group,

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding N-oxide thereof, or a correspondingsalt thereof, or a corresponding solvate thereof,

whereby preferably the following provisos (disclaimers) apply:

that R⁴ and R⁵ do not both represent a hydrogen atom, and that if one ofthe residues R⁴ and R⁵ represents a hydrogen atom or a linear orbranched, saturated or unsaturated; substituted or unsubstitutedaliphatic group, the other one of these residues R⁴ and R⁵ does notrepresent a substituted or unsubstituted pyridyl group, a substituted orunsubstituted pyrimidyl group, a substituted or unsubstituted pyridazylgroup, a substituted or unsubstituted, pyrazinyl group, a substituted orunsubstituted thienyl group, a substituted or unsubstituted benzylgroup, a substituted or unsubstituted phenethyl group, a substituted orunsubstituted phenyl group, a substituted or unsubstituted phenyl group,which is condensed (attached) to at least one, optionally substitutedring or ringsystem, an —NH-phenyl-moiety, wherein the phenyl group maybe at least mono-substituted, an unsubstituted or substituted thiazolegroup, or an unsubstituted or substituted [1,3,4]thiadiazole group.

Preferred are also substituted pyrazoline compounds of general formula Igiven above, wherein R¹ represents a phenyl group, which is optionallysubstituted by one or more substituents independently selected from thegroup consisting of a linear or branched C₁₋₆-alkyl group, a linear orbranched C₁₋₆-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH,NO₂, —C═O)—R′, SH, SR′, SOR′, SO₂R′, NH₂, NHR′, NR′R″, —(C═O)—NH₂,—(C═O)NHR′ and —(C═O)—NR′R″, whereby R′ and R″ for each substituentindependently represent linear or branched C₁₋₆ alkyl, preferably R¹represents a phenyl group, which is optionally substituted by one ormore substituents selected from the group consisting of methyl, ethyl,F, Cl, Br and CF₃, more preferably R¹ represents a phenyl group, whichis substituted with a chlorine atom in the 4-position, and R²-R⁸ havethe meaning given above, optionally in form of one of the stereoisomers,preferably enantiomers or diastereomers, a racemate or in form of amixture of at least two of the stereoisomers, preferably enantiomersand/or diastereomers, in any mixing ratio, or a corresponding N-oxidethereof, or a corresponding salt thereof, or a corresponding solvatethereof.

Also preferred are substituted pyrazoline compounds of general formula Igiven above, wherein R² represents a phenyl group, which is optionallysubstituted by one or more substituents independently selected from thegroup consisting of a linear or branched C₁₋₆-alkyl group, a linear orbranched C₁₋₆-alkoxy group, a halogen atom, CH₂F, CHF₂, CF₃, CN, OH,NO₂, —(C═O)—R′, SH, SR′, SOR′, SO₂R′, NH₂, NHR′, NR′R″, —(C═O)—NH₂,—(C═O)—NHR′ and —(C═O)NR′R″ whereby R′ and R″ for each substituentindependently represent linear or branched C₁₋₆ alkyl, preferably R²represents a phenyl group, which is optionally substituted by one ormore substituents selected from the group consisting of methyl, ethyl,F, Cl, Br and CF₃, more preferably R² a phenyl group, which isdi-substituted with two chlorine atoms in the 2- and 4-position, and R¹and R³-R⁸ have the meaning given above, optionally in form of one of thestereoisomers, preferably enantiomers or diastereomers, a racemate or inform of a mixture of at least two of the stereoisomers, preferablyenantiomers and/or diastereomers, in any mixing ratio, or acorresponding N-oxide thereof, or a corresponding salt thereof, or acorresponding solvate thereof.

Preference is also given-to substituted pyrazoline compounds of generalformula I given above, wherein R³ represents a saturated or unsaturated,optionally at least mono-substituted, optionally at least one heteroatomas ring member containing C₃₋₈ cycloaliphatic group, which may becondensed with an optionally at least mono- substituted mono- orpolycyclic ring system, or R³ represents an optionally at leastmono-substituted, 5- or 6-membered aryl or heteroaryl group, which maybe condensed with an optionally at least mono-substituted mono- orpolycyclic ring system, or R³ represents an —NR⁴R⁵-moiety, preferably R³represents a saturated, optionally at least mono-substituted, optionallyone or more nitrogen-atoms as ring member containing C₃₋₈ cycloaliphaticgroup, which may be condensed with an optionally at leastmono-substituted mono- or polycyclic ring system, or R³ represents an—NR⁴R⁵-moiety, more preferably R³ represents a pyrrolidinyl group apiperidinyl group or a piperazinyl group, whereby each of these groupsmay be substituted with one or more C₁₋₆-alkyl groups, or R³ representsan —NR⁴R⁵-moiety and R¹, R² and R⁴-R⁸ have the meaning given above,optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding N-oxide thereof, or a correspondingsalt thereof, or a corresponding solvate thereof.

Furthermore, substituted pyrazoline compounds of general formula I givenabove are preferred, wherein R⁴ and R⁵, identical or different,represent a hydrogen atom, an unbranched or branched, saturated orunsaturated, optionally at least mono-substituted C₁₋₆-aliphaticradical, a saturated or unsaturated, optionally at leastmono-substituted, optionally at least one heteroatom as ring membercontaining C₃₋₈-cycloaliphatic group, which may be condensed with anoptionally at least mono-substituted mono- or polycyclic ring system, oran optionally at least mono-substituted, 5- or 6-membered aryl orheteroaryl group, which may be condensed with an optionally at leastmono-substituted mono- or polycyclic ring system and/or bonded via amethylene (—CH₂—) or ethylene (—CH₂—CH₂)-group, an —O₂-R⁶-moiety, or an—NR⁷R⁸-moiety, preferably one of these residues R⁴ and R⁵ represents ahydrogen atom and the other one of these residues R⁴ and R⁵ represents asaturated or unsaturated, optionally at least mono-substituted,optionally at least one heteroatom as ring member containingC₃₋₈-cycloaliphatic group, which may be condensed with an optionally atleast mono-substituted mono- or polycyclic ring system, or an optionallyat least mono-substituted, 5 or 6-membered aryl or heteroaryl groupwhich may be condensed with an optionally at least mono-substitutedmono- or polycyclic ring system, an —SO₂-R⁶-moiety, or an —NR⁷R⁸-moiety,or R⁴ and R⁵, identical or different, each represent a C₁₋₆ alkyl group,more preferably one of these residues R⁴ and R⁵ represents a hydrogenatom and the other one of these residues R⁴ and R⁵ represents anoptionally at least mono-substituted pyrrolidinyl group, an optionallyat least mono-substituted piperidinyl group, an optionally at leastmono-substituted piperazinyl group, an optionally at leastmono-substituted triazolyl group, an —SO₂-R⁶-moiety, or an—NR⁷R⁸-moiety, or R⁴ and R⁵, identical or different, represent a methylgroup, an ethyl group, an n-propyl group, an isopropyl group, an n-butylgroup, a sec-butyl group or a tert-butyl group, and R¹-R³ and R⁶-R⁸ havethe meaning given above, optionally in form of one of the stereoisomers,preferably enantiomers or diastereomers, a racemate or in form of amixture of at least two of the stereoisomers, preferably enantiomersand/or diastereomers, in any mixing ratio, or a corresponding N-oxidethereof, or a corresponding salt thereof, or a corresponding solvatethereof.

Also preferred are substituted pyrazoline compounds of general formula Igiven above, wherein R⁶ represents a linear or branched saturated orunsaturated, optionally at least mono-substituted C₁₋₆ aliphatic group,a saturated or unsaturated, optionally at least mono-substituted,optionally at least one heteroatom as ring member containing C₃₋₈cycloaliphatic group, which may be condensed with a mono- or polycyclicring-system, or an optionally at least mono-substituted, 5- or6-membered aryl or heteroaryl group, which may be condensed with a mono-or polycyclic ring system and/or bonded via a methylene (—CH₂—) orethylene (—CH₂—CH₂)-group, preferably R⁶ represents a C₁₋₆-alkyl group,a saturated, optionally at least mono-substituted cycloaliphatic group,which may be condensed with a mono- or polycyclic ring-system, or aphenyl group, which is optionally substituted with one or more C₁₋₆alkyl groups, and R¹-R⁵, R⁷ and R⁸ have the meaning given above,optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding N-oxide thereof, or a correspondingsalt thereof, or a corresponding solvate thereof.

Moreover substituted pyrazoline compounds of general formula I givenabove are preferred, wherein R⁷ and R⁸, identical or different,represent a hydrogen atom, an unbranched or branched, saturated orunsaturated, optionally at least mono-substituted C₁₋₆aliphatic-radical, a saturated or unsaturated, optionally at leastmono-substituted, optionally at least one heteroatom as ring membercontaining C₃₋₈ cycloaliphatic group, which may be condensed with anoptionally at least mono-substituted mono- or polycyclic ring system, oran optionally at least mono-substituted, 5- or 6 membered aryl orheteroaryl group, which may be condensed with an optionally at leastmono-substituted mono- or polycyclic ring system and/or bonded via amethylene (—CH₂—) or ethylene (—CH₂CH₂)-group, preferably represent ahydrogen atom or a C₁₋₆ alkyl radical, and R¹-R⁶ have the meaning givenabove, optionally in form of one of the stereoisomers, preferablyenantiomers or diastereomers, a racemate or in form of a mixture of atleast two of the stereoisomers, preferably enantiomers and/ordiastereomers, in any mixing ratio, or a corresponding N-oxide thereof,or a corresponding salt thereof, or a corresponding solvate thereof.

Particularly preferred are compounds of general formula I given below,

wherein

R¹ represents a phenyl ring, which is mono-substituted with a halogenatom, preferably a chlorine atom, in its 4-position,

R² represents a phenyl ring, which is di-substituted with two halogenatoms, preferably chlorine atoms, in its 2- and 4-position,

R³ represents a pyrrolidinyl group, a piperidinyl group, a piperazinylgroup, a homo-piperazinyl group, a morpholinyl group, or an—NR⁴R⁵-moiety,

R⁴ represents a hydrogen atom or a linear or branched C₁₋₆-alkyl group,

R⁵ represents a linear or branched C₁₋₆ alkyl group, a pyrrolidinylgroup, a piperdinyl group, a piperazinyl group, a homo-piperazinylgroup, a morpholinyl group, a triazolyl group, whereby each of theheterocyclic rings may be substituted with one or more, identical ordifferent, C₁₋₆-alkyl groups, or an —SO₂-R⁶-moiety, and

R⁶ represents a phenyl group, which is optionally substituted with oneor more C₁₋₆ alkyl groups, which may be identical or different,

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding N-oxide thereof, or a correspondingsalt thereof, or a corresponding solvate thereof.

Most particularly preferred are substituted pyrazoline compoundsselected from the group consisting of:

N-piperidinyl-5-4-chloro-phenyl)-1-(2,4-dichlorophenyl-4,5-dihydro-1H-pyrazol-3-carboxamide,

5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylicacid-[1,2,4]-triazole-4-yl-amide,

5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylicacid-(4-methyl-piperazin-1-yl)-amide,

5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylicacid diethylamide,

[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-yl]-piperidine-1-yl-methanone,

N-[5-(4-Chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl]-4-methylphenylsufonamide,

optionally in the form of a corresponding N-oxide, or a correspondingsalt, or a corresponding solvate.

In another aspect the present invention also provides a process for thepreparation of substituted pyrazoline compounds of general formula givenabove, according to which at least one benzaldehyde compound of generalformula II

wherein R¹ has the meaning given above, is reacted with a pyruvatecompound of general formula (III)

wherein R is a branched or unbranched C₁₋₆ alkyl radical, to yield acompound of general formula (IV)

wherein R¹ has the meaning given above, which is optionally isolatedand/or optionally purified, and which is reacted with an optionallysubstituted phenyl hydrazine of general formula (V).

or a corresponding salt thereof, wherein R² has the meaning given above,under an inert atmosphere, to yield a compound of general formula (VI)

wherein R¹ and R² have the meaning as given above, which is optionallyisolated and/or optionally purified, and optionally transferred underinert atmosphere to a compound of general formula (VII)

wherein the substituents R¹ and R² have the meaning given above and Arepresents a leaving group via the reaction with an activating agent,said compound being optionally isolated and/or optionally purified, andat least one compound of general formula (VI) is reacted with a compoundof general formula R³H, wherein R³ represents an —NR⁴R⁵-moiety, whereinR⁴ and R⁵ have the meaning given above, to yield a substitutedpyrazoline compound of general formula I, wherein R³ represents an—NR⁴R⁵-moiety,

and/or at least one compound of general formula (VII) is reacted with acompound of the general formula R³H, in which R³ has the meaning givenabove to yield a compound of general formula (I) given above, which isoptionally isolated and/or optionally purified.

The inventive process is also illustrated in scheme I given below:

The reaction of the benzaldehyde compound of general formula II with apyruvate compound of general formula III is preferably carried out inthe presence of at least one base, more preferably in the presence of analkali metal hydroxide such as sodium hydroxide or potassium hydroxideor an alkali metal methoxide such as sodium methoxide, as described, forexample, in Synthetic communications, 26(11), 2229-33, (1996). Therespective description is hereby incorporated by reference and formspart of the disclosure. Preferably said reaction is carried out in aprotic reaction medium such as a C₁₋₄ alkyl alcohol or mixtures ofthese.

Reaction temperature as well as the duration of the reaction may varyover a broad range. Preferred reaction temperatures range from −10° C.to the boiling point of the reaction medium. Suitable reaction times mayvary for example from several minutes to several hours.

Also preferred the reaction of the benzaldehyde compound of generalformula II with a pyruvate compound of general formula III is carriedout under acid catalysed conditions, more preferably by refluxing themixture in dichloromethane in the presence ofcopper(II)trifluoromethanesulfonate as described, for example, inSynlett, (1), 147-149, 2001. The respective description is herebyincorporated by reference and forms part of the disclosure.

The reaction of the compound of general formula (IV) with an optionallysubstituted phenyl hydrazin of general formula (V) is preferably carriedout in a suitable reaction medium such as C₁₋₄-alcohols or ethers suchas dioxane or tetrahydrofurane or mixtures of at least two of theseafore mentioned compounds. Also preferably, said reaction may be carriedout in the presence of an acid, whereby the acid may be organic such asacetic acid and/or inorganic such as hydrochloric acid. Furthermore, thereaction may also be carried out in the presence of a base such aspiperidine, piperazine, sodium hydroxide, potassium hydroxide, sodiummethoxide or sodium ethoxide, or a mixture of at least two of thesebases may also be used.

Reaction temperature as well as the duration of the reaction may varyover a broad range. Suitable reaction temperatures range from roomtemperature, i.e. approximately 25° C. to the boiling point of thereaction medium. Suitable reaction times may vary for example fromseveral minutes to several hours.

The carboxylic group of the compound of general formula (VI) may beactivated for further reactions by the introduction of a suitableleaving group according to conventional methods well known to thoseskilled in the art. Preferably the compounds of general formula (VI) aretransferred into an acid chloride, an acid anhydride, a mixed anhydride,a C₁₋₄ alkyl ester, an activated ester such as p-nitrophenylester. Otherwell known methods for the activation of acids include the activationwith N,N-dicyclohexylcarbodiimide orbenzotriazol-N-oxotris(dimethylamino)phosphonium hexafluorophosphate(BOP)).

If said activated compound of general formula (VII) is an acid chloride,it is preferably prepared by reaction of the corresponding acid ofgeneral formula (VI) with thionyl chloride or oxalyl chloride, wherebysaid chlorinating agent is also used as the solvent Also preferably anadditional solvent may be used. Suitable solvents include hydrocarbonssuch as benzene, toluene or xylene, halogenated hydrocarbons such asdichloromethane, chloroform or carbon tetrachloride, ethers such asdiethyl ether, dioxane, tetrahydrofurane or dimethoxyethane. Mixtures oftwo or more solvents from one class or two or more solvents fromdifferent classes may also be used. Preferred reaction temperature rangefrom 0° C. to the boiling point of the solvent and reaction times fromseveral minutes to several hours.

If said activated compound of general formula (VII) is admixedanhydride, said anhydride may preferably be prepared, for example, byreaction of the corresponding acid of general formula (VI) with ethylchloroformiate in the presence of a base such as triethylamine orpyridine, in a suitable solvent.

The reaction of general formula (VII) with a compound of general formulaHR³ to yield compounds of general general I, wherein R³ represents an—NR⁴R⁵ moiety is preferably carried out in presence of a base such astriethylamine in a reaction medium such as methylenechloride. Thetemperature is preferably in the range from 0° C. to the boiling pointof the reaction medium. The reaction time may vary over a broad range,e.g. from several hours to several days.

The reaction of general formula (VII) with a compound of general formulaHR³ to yield compounds of general formula I, wherein R³ represents asaturated or unsaturated, optionally at least mono-substituted,optionally at least one heteroatom as ring member containingcycloaliphatic group, which may be condensed with an optionally at leastmono-substituted mono- or polycyclic ring system, or an optionally atleast mono-substituted aryl or heteroaryl group, which may be condensedwith an optionally at least mono-substituted mono- or polycyclic ringsystem may be carried out according to conventional methods well knownto those skilled in the art, e.g. from Pascual, A., J. Prakt Chem.,1999, 341(7), 695-700; Lin, S. et al., Heterocycles, 2001, 55(2),265-277; Rao, P. et al., J. Org. Chem., 2000, 65(22), 7323-7344, PearsonD. E. and Buehler, C. A., Synthesis, 1972, 533-542 and references citedtherein. The respective descriptions are hereby incorporated byreference and form part of the present disclosure.

Preferably said reaction is carried out in the presence of a Lewis acid,which is preferably selected from the group consisting of FeCl₃, ZnCl₂and AlCl₃, in a suitable reaction medium such as toluene, benzene,tetrahydrofurane or similar. The temperature is preferably in teh rangefrom 0° C. to the boiling point of the reaction medium, more preferablyfrom 15 to 25° C. The reaction time may vary over a broad range, e.g.from several minutes to several hours.

The afore mentioned reactions involving the synthesis of the4,5-dihydro-pyrazole ring or the reaction of a compound comprising saidring are carried out under an inert atmosphere, preferably nitrogen orargon, to avoid oxidation of the ring-system.

During the processes described above the protection of sensitive groupsor of reagents may be necessary and/or desirable. The introduction ofconventional protective groups as well as their removal may be performedby methods well-known to those skilled in the art.

If the substituted pyrazoline compounds of general formula (I)themselves are obtained in form of a mixture of stereoisomers,particularly enantiomers or diastereomers, said mixtures may beseparated by standard procedures known to those skilled in the art, e.g.chromatographic methods or fractunalized crystallization with chiralreagents. It is also possible to obtain pure stereoisomers viastereoselective synthesis.

In a further aspect the present invention also provides a process forthe preparation of salts of substituted pyrazoline compounds of generalformula (I) and stereoisomers thereof, wherein at least one compound ofgeneral formula (I) having at least one basic group is reacted with atleast one inorganic and/or organic acid, preferably in the presence of asuitable reaction medium. Suitable reaction media include, for example,any of the ones given above. Suitable inorganic acids includehydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid,nitric acid, suitable organic acids are e.g. citric acid, maleic acid,fumaric acid, tartaric acid, or derivatives thereof, p-toluenesulfonicacid, methanesulfonic acid or camphersulfonic acid.

In yet a further-aspect the present invention also provides a processfor the preparation of salts of substituted pyrazoline compounds ofgeneral formula (I) or stereoisomers thereof, wherein at least onecompound of general formula (I) having at least one acidic group isreacted with one or more suitable bases, preferably in the presence of asuitable reaction medium. Suitable bases are e.g. hydroxides, carbonatesor alkoxides, which include suitable cations, derived e.g. from alkalinemetals, alkaline earth metals or organic cations, e.g. [NH_(n)R_(4-n)]⁺,wherein n is 0, 1, 2, 3 or 4 and R represents a branched or unbranchedC₁₋₄-alkyl-radical. Suitable reaction media are, for example, any of theones given above.

Solvates, preferably hydrates, of the substituted pyrazoline compoundsof general formula (I), of corresponding stereoisomers, of correspondingN-oxides or of corresponding salts thereof may also be obtained bystandard procedures known to those skilled in the art.

Substituted pyrazoline compounds of general formula I, which comprisenitrogen-atom containing saturated, unsaturated or aromatic rings mayalso be obtained in the form of their N-oxides by methods well known tothose skilled in the art.

The purification and isolation of the inventive substituted pyrazolinecompounds of general formula (I), of a corresponding stereoisomer, orsalt, or solvate or any intermediate thereof may, if required, becarried out by conventional methods known to those skilled in the art,e.g. chromatographic methods or recrystallization.

The substituted pyrazoline compounds of general formula (I) given below,their stereoisomers, corresponding N-oxides, corresponding salts thereofand corresponding solvates are toxicologically acceptable and aretherefore suitable as pharmaceutical active substances for thepreparation of medicaments.

It has been found that the substituted pyrazoline compounds of generalformula I given below, stereoisomers thereof, N-oxides thereof,corresponding salts and corresponding solvates have a high affinity tocannabinoid receptors, particularly cannabinoid 1 (CB₁)-receptors, i.e.they act as antagonists on these receptors. In particular thesepyrazoline compounds show little or no development of tolerance duringtreatment particularly with respect to food intake. After ending thetreatment with the pyrazoline compounds, reduced increase of body weightis found compared to the pre-treatment level.

Thus, an other aspect of the present invention relates to a medicamentcomprising at least one substituted pyrazoline-compound of generalformula I,

wherein

R¹ represents an optionally at least mono-substituted phenyl group,

R² represents an optionally at least mono-substituted phenyl group,

R³ represents a saturated or unsaturated, optionally at leastmono-substituted, optionally at least one heteroatom as ring membercontaining cycloaliphatic group, which may be condensed with anoptionally at least mono-substituted mono- or polycyclic ring system, orR³ represents an optionally at least mono-substituted aryl or heteroarylgroup, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or R³ represents an—NR⁴R⁵-moiety,

R⁴ and R⁵, identical or different, represent a hydrogen atom, anunbranched or branched, saturated or unsaturated, optionally at leastmono-substituted aliphatic radical, a saturated or unsaturated,optionally at least mono-substituted, optionally at least one heteroatomas ring member containing cycloaliphatic group, which may be condensedwith an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono-substituted aryl or heteroarylgroup, which may be condensed with an optionally at leastmono-substituted mono- or polycyclic ring system and/or bonded via alinear or branched alkylene group, an —SO₂-R⁶-moiety, or an—NR⁷R⁸-moiety, with the proviso that R⁴ and R⁵ do not identicallyrepresent hydrogen,

R⁶ represents a linear or branched, saturated or unsaturated, optionallyat least mono-substituted aliphatic group, a saturated or unsaturated,optionally at least mono-substituted, optionally at least one heteroatomas ring member containing cycloaliphatic group, which may be condensedwith a mono- or polycyclic ring-system, or an optionally at leastmono-substituted aryl or heteroaryl group, which may be condensed with amono- or polycyclic ring system and/or bonded via a linear or branchedalkylene group,

R⁷ and R⁸, identical or different, represent a hydrogen atom, anunbranched or branched, saturated or unsaturated, optionally at leastmono-substituted aliphatic radical, a saturated or unsaturated,optionally at least mono-substituted, optionally at least one heteroatomas ring member containing cycloaliphatic group, which may be condensedwith an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono-substituted aryl or heteroarylgroup, which may be condensed with an optionally at leastmono-substituted mono- or polycyclic ring system and/or bonded via alinear or branched alkylene group, optionally in form of one of thestereoisomers, preferably enantiomers or diastereomers, a racemate or inform of a mixture of at least two of the stereoisomers, preferablyenantiomers and/or diastereomers, in any mixing ratio, or acorresponding N-oxide thereof, or a corresponding salt thereof, or acorresponding solvate thereof, and optionally one or morepharmaceutically acceptable excipients.

A mono- or polycyclic ring-system according to the present inventionmeans a mono- or polycyclic hydrocarbon ring-system that may besaturated, unsaturated or aromatic. If the ring system is polycyclic,each of its different rings may show a different degree of saturation,i.e. it may be saturated, unsaturated or aromatic. Optionally each ofthe rings of the mono- or polycyclic ring system may contain one or moreheteroatoms as ring members, which may be identical or different andwhich can preferably be selected from the group consisting of N, O, Sand P, more preferably be selected from the group consisting of N, O andS. Preferably the polycyclic ring-system may comprise two rings that arecondensed. The rings of the mono- or polycyclic ring-system arepreferably 5 or 6-membered. The term “condensed” according to thepresent invention means that a ring or ring-system is attached toanother ring or ring-system, whereby the terms “annulated” or“annelated” are also used by those skilled in the art to designate thiskind of attachment.

If one or more of the residues R³-R⁸ represents or comprises a saturatedor unsaturated, optionally at least one heteroatom as ring membercontaining cycloaliphatic group, which is substituted by one or moresubstituents, unless defined otherwise, each of the substituents may beindependently selected from the group consisting of hydroxy, fluorine,chlorine, bromine, branched or unbranched C₁₋₆-alkoxy, branched orunbranched C₁₋₆-alkyl, unbranched C₁₋₄-perfluoroalkoxy, branched orunbranched C₁₋₄-perfluoroalkyl, oxo, amino, carboxy, amido, cyano,nitro, —SO₂NH₂, —CO—C₁₋₄-alkyl, —SO—C₁₋₄-alkyl, —SO₂—C₁₋₄-alkyl,—NH—SO₂—C₁₋₄-alkyl, wherein the C₁₋₄-alkyl may in each case be branchedor unbranched, and a phenyl group, more preferably be selected from thegroup consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy,oxo, CF₃ and a phenyl group.

If one or more of the residues R³-R⁸ represents or comprises acycloaliphatic group, which contains one or more heteroatoms as ringmembers, unless defined otherwise, each of these heteroatoms maypreferably be selected from the group consisting of of N, O and S.

Suitable saturated or unsaturated, optionally at least one heteroatom asring member containing, optionally at least mono-substitutedcycloaliphatic groups may preferably be selected from the groupconsisting of Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl,Cycloheptyl, Cyclooctyl, Cyclopentenyl, Cyclohexenyl, Cycloheptenyl,Cyclooctenyl, Pyrrolidinyl, Piperidinyl, Piperazinyl, homo-Piperazinyland Morpholinyl.

If one or more of the residues R³-R⁸ comprises a mono- or polycyclicring system, which is substituted by one or more substituents, unlessdefined otherwise, each of the substituents may be independentlyselected from the group consisting of hydroxy, fluorine, chlorine,bromine, branched or unbranched C₁₋₆-alkoxy, branched or unbranchedC₁₋₆-alkyl, branched or unbranched C₁₋₄-perfluoroalkoxy, branched orunbranched C₁₋₄-perfluoroalkyl, amino, carboxy, oxo, amido, cyano,nitro, —SO₂NH₂, —CO—C₁₋₄-alkyl, —SO—C₁₋₄-alkyl, —SO₂—C₁₋₄-alkyl,—NH—SO₂—C₁₋₄-alkyl, wherein the C₁₋₄-alkyl may in each case be branchedor unbranched, and a phenyl group, more preferably be selected from thegroup consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy,CF₃, oxo and a phenyl group.

If one or more of the residues R¹-R⁸ represents or comprises an arylgroup, including a phenyl group, which is substituted by one or moresubstituents, unless defined otherwise, each of the substituents may beindependently selected from the group consisting of a halogen atom, alinear or branched C₁₋₆-alkyl group, a linear or branched C₁₋₆ alcoxygroup, a fonnyl group, a hydroxy group, a trifluoromethyl group, atrifluoromethoxy group, a —CO—C₁₋₆-alkyl group, a cyano group, a nitrogroup, a carboxy group, a —CO—O—C₁₋₆-alkyl group, a —CO—NR^(A)R^(B)—moiety, a —CO—NH—NR^(C)R^(D)-moiety, an —SH, an —S—C₁₋₆-alkyl group, an—SO—C₁₋₆-alkyl group, an —SO₂—C₁₋₆-alkyl group, a—C₁₋₆-alkylene-S—C₁₋₆-alkyl group, a —C₁₋₆-alkylene-SO—C₁₋₆-alkyl group,a —C₁₋₆-alkylene-SO₂—C₁₋₆-alkyl group, an —NH₂-moiety, an NHR′-moiety oran NR′R″-moiety, wherein R′ and R″ independently represent a linear orbranched C₁₋₆-alkyl group, a C₁₋₆-alkyl group substituted by one or morehydroxy groups and a —C₁₋₆-alkylene-NR^(E)R^(F) group,

whereby R^(A), R^(B), identical or different, represent hydrogen or aC₁₋₆-alkyl group, or R^(A) and R^(B) together with the bridging nitrogenatom form a saturated, mono- or bicyclic, 3-10 membered heterocyclicring system, which may be at least mono-substituted by one or more,identical or different, C₁₋₆ alkyl groups and/or which may contain atleast one further heteroatom selected from the group consisting ofnitrogen, oxygen and sulphur as a ring member,

R^(C), R^(D), identical or different, represent a hydrogen atom, aC₁₋₆-alkyl group, a —CO—O—C₁₋₆-alkyl group, a C₃₋₈-cycloalkyl group, aC₁₋₆-alkylene-C₃₋₈-cycloalkyl group, C₁₋₆-alkylene-O—C₁₋₆-alkyl group ora C₁₋₆-alkyl group substituted with one or more hydroxy groups, orR^(C), R^(D) together with the bridging nitrogen atom form a saturated,mono- or bicyclic, 3-10 membered heterocyclic ring system, which may beat least mono-substituted by one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl group, a —CO—C₁₋₆-alkylgroup, a —CO—O—C₁₋₆-alkyl group, a —CO—NH—C₁₋₆-alkyl group, a—CS—NH—C₁₋₆-alkyl group, an oxo group, a C₁₋₆-alkyl group substitutedwith one or more hydroxy groups, a C₁₋₆-alkylene-O—C₁₋₆-alkyl group anda —CO—NH₂ group and/or which may contain at least one further heteroatomselected from the group consisting of nitrogen, oxygen and sulphur as aring member, and

wherein R^(E), R^(F), identical or different, represent hydrogen or aC₁₋₆-alkyl group, or R^(E) and R^(F) together with the bridging nitrogenatom form a saturated, mono- or bicyclic, 3-10 membered heterocyclicring system, which may be at least mono-substituted by one or more,identical or different C₁₋₆ alkyl groups and/or which may contain atleast one further heteroatom selected from the group consisting ofnitrogen, oxygen and sulphur as a ring member.

Preferred aryl groups, which may optionally be at leastmono-substituted, are phenyl and naphthyl.

If one or more of the residues R³-R⁸ represents or comprises aheteroaryl group, which is substituted by one or more substituents,unless defined otherwise, each of the substituents may be independentlyselected from the group consisting of a halogen atom, a linear orbranched C₁₋₆-alkyl group, a linear or b ranched C₁₋₆ alcoxy group, aformyl group, a hydroxy group, a trifluoromethyl group, atrifluoromethoxy group, a —CO—C₁₋₆-alkyl group, a cyano group, a carboxygroup, a —CO—O—C₁₋₆-alkyl group, a —CO—NR^(A)R^(B)-moiety, a—CO—NH—NR^(C)R^(D)-moiety, an —S—C₁₋₆-alkyl group, an —SO—C₁₋₆-alkylgroup, an —SO₂—C₁₋₆-alkyl group, a —C₁₋₆-alkylene-S—C_(C) ₁₋₆-alkylgroup, a —C₁₋₆-alkylene-SO—C₁₋₆-alkyl group, a—C₁₋₆-alkylene-SO₂—C₁₋₆-alkyl group, a C₁₋₆-alkyl group substituted byone or more hydroxy groups and a —C₁₋₆-alkylene-NR^(E)R^(F) group,

whereby R^(A), R^(B), identical or different, represent hydrogen or aC₁₋₆-alkyl group, or R^(A) and R^(B) together with the bridging nitrogenatom form a saturated, mono- or bicyclic, 3-10 membered heterocyclicring-system, which may be at least mono-substituted by one or more,identical or different, C₁₋₆ alkyl groups and/or which may contain atleast one further heteroatom selected from the group consisting ofnitrogen, oxygen and sulphur as a ring member,

R^(C), R^(D), identical or different, represent a hydrogen atom, aC₁₋₆-alkyl group, a —CO—O—C₁₋₆-alkyl group, a C₃₋₈-cycloalkyl group, aC₁₋₆-alkylene-C₃₋₈-cycloalkyl group, C₁₋₆-alkylene-O—C₁₋₆-alkyl group ora C₁₋₆-alkyl group substituted with one or more hydroxy groups, orR^(C), R^(D) together with the bridging nitrogen atom form a saturated,mono- or bicyclic, 3-10 membered heterocyclic ring system, which may beat least mono-substituted by one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl group, a —CO—C₁₋₆-alkylgroup, a —CO—O—C₁₋₆-alkyl group, a —CO—NH—C₁₋₆-alkyl group, a—CS—NH—C₁₋₆-alkyl group, an oxo group, a C₁₋₆-alkyl group substitutedwith one or more hydroxy groups, a C₁₋₆-alkylene-O—C₁₋₆-alkyl group anda —CO—NH₂ group and/or which may contain at least one further heteroatomselected from the group consisting of nitrogen, oxygen and sulphur as aring member, and

wherein R^(E), R^(F), identical or different, represent hydrogen or aC₁₋₆-alkyl group, or R^(E) and R^(F) together with the bridging nitrogenatom form a saturated, mono- or bicyclic, 3-10 membered heterocyclicring system, which may be at least mono-substituted by one or more,identical or different C₁₋₆ alkyl groups and/or which may contain atleast one further heteroatom selected from the group consisting ofnitrogen, oxygen and sulphur as a ring member,

The heteroatoms, which are present as ring members in the heteroarylradical, may, unless defined otherwise, independently be selected fromthe group consisting of nitrogen, oxygen and sulphur.

Suitable heteroaryl groups which may optionally be at leastmono-substituted, may preferably be selected from the group consistingof thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrimidinyl,pyrazinyl, indolyl, chinolinyl, isochinolinyl,benzo[1,2,5]-thiodiazolyl, benzo[b]thiophenyl, benzo[b]furanyl,imidazo[2,1-b]thiazolyl, triazolyl, and pyrazolyl, more preferably beselected from the group consisting of thienyl-,benzo[1,2,5]-thiodiazolyl benzo[b]thiophenyl, imidazo[2,1-b]thiazolyl,triazolyl and pyrazolyl.

If one or more of the residues R⁴-R⁸ represents or comprises a linear orbranched, saturated or unsaturated aliphatic group, which is substitutedby one or more substituents, unless defined otherwise, each of thesubstituents may be independently selected from the group consisting ofhydroxy, fluorine, chlorine, bromine, branched or unbranchedC₁₋₄-alkoxy, branched or unbranched C₁₋₄-perfluoroalkoxy, branched orunbranched C₁₋₄-perfluoroalkyl, amino, carboxy, amido, cyano, nitro,—SO₂NH₂, —CO—C₁₋₄-alkyl, —SO—C₁₋₄-alkyl, —SO₂—C₁₋₄-alkyl,—NH—SO₂—C₁₋₄-alkyl, wherein the C₁₋₄-alkyl may in each case be branchedor unbranched, and a phenyl group, more preferably be selected from thegroup consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, CF₃ and aphenyl group.

Preferred linear or branched, saturated or unsaturated aliphatic groups,which may be substituted by one or more substituents, may preferably beselected from the group consisting of methyl, ethyl, n-propyl,isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl,n-heptyl, n-octyl, n-nonyl, n-decyl, vinyl, ethinyl, propenyl, propinyl,butenyl and butinyl.

If any of the residues R⁴-R⁸ represents or comprises a linear orbranched alkylene group, said alkylene group may preferably be selectedfrom the group consisting of -methylene-(CH₂)—, ethylene —(CH₂—CH₂)—,n-propylene —(CH₂—CH₂—CH₂)— or iso-proylene —C(CH₃)₂)—.

The inventive medicament may preferably also comprise any of theinventive pyrazoline compounds or combinations of at least two of thesepyrazoline compounds given above.

Said medicament may also comprise any combination of one or more of thesubstituted pyrazoline compounds of general formula I given above,stereoisomers thereof, corresponding N-oxides thereof, physiologicallyacceptable salts thereof or physiologically acceptable solvates thereof.

Preferably said medicament is suitable for the modulation (regulation)of cannabinoid-receptors, preferably cannabinoid 1 (CB₁) receptors, forthe prophylaxis and/or treatment of disorders of the central nervoussystem, disorders of the immune system, disorders of the cardiovascularsystem, disorders of the endocrinous system, disorders of therespiratory system, disorders of the gastrointestinal tract orreproductive disorders.

Particularly preferably said medicament is suitable for the prophylaxisand/or treatment of psychosis.

Also particularly preferably said medicament is suitable for theprophylaxis and/or treatment of food intake disorders, preferablybulimia, anorexia, cachexia, obesity and/or type II diabetus mellitus(non-insuline dependent diabetes mellitus), preferably obesity.

Particularly preferably said medicament is suitable for the prophylaxisand/or treatment of alcohol abuse and/or alcohol addiction, nicotineabuse and/or nicotine addiction, drug abuse and/or drug addiction and/ormedicament abuse and/or medicament addiction, preferably drug abuseand/or drug addiction.

Medicaments and/or drugs, which are frequently the subject of misuseinclude opioids, barbiturates, cannabis, cocaine, amphetamines,phencyclidine, hallucinogens and benzodiazepines.

The medicament is also suitable for the prophylaxis and/or treatment ofone or more disorders selected from the group consisting ofschizophrenia, anxiety, depression, epilepsy, neurodegenerativedisorders, cerebellar disorders, spinocerebellar disorders, cognitivedisorders, cranial trauma, panic attacks, peripheric neuropathy,inflammation, glaucoma, migraine, Morbus Parkinson, Morbus Huntington,Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsivedisorders, senile dementia, thymic disorders, tardive dyskinesia,bipolar disorders, cancer, medicament-induced movement disorders,dystonia, endotoxemic shock, hemorragic shock, hypotension, insomnia,immunologic disorders, sclerotic plaques, vomiting, diarrhea, asthma,memory disorders, pruritus, pain, or for potentiation of the analgesiceffect of narcotic and non-narcotic analgesics, or for influencingintestinal transit.

Another aspect of the present invention is the use of at least onesubstituted pyrazoline compound of general formula I given above assuitable active substances for the medicament, optionally in form of oneof the stereoisomers, preferably enantiomers or diastereomers, aracemate or in form of a mixture of at least two of the stereoisomers,preferably enantiomers and/or diastereomers, in any mixing ratio, or acorresponding N-oxide-thereof, or a corresponding salt thereof, or acorresponding solvate thereof, and optionally one or morepharmaceutically acceptable excipients, for the preparation of amedicament for the modulation of cannabinoid-receptors, preferablycannabinoid 1 (CB₁) receptors, for the prophylaxis and/or treatment ofdisorders of the central nervous system, disorders of the immune system,disorders of the cardiovascular system, disorders of the endocrinoussystem, disorders of the respiratory system, disorders of thegastrointestinal tract or reproductive disorders.

Particularly preferred is the use of at least one of the respectivepyrazoline compounds, optionally in form of one of the stereoisomers,preferably enantiomers or diastereomers, a racemate or in form of amixture of at least two of the stereoisomers, preferably enantiomersand/or diastereomers, in any mixing ratio, or a corresponding N-oxidethereof, or a corresponding salt thereof, or a corresponding solvatethereof, and optionally one or more pharmaceutically acceptableexcipients, for the preparation of a medicament for the prophylaxisand/or treatment of psychosis.

Also particularly preferred is the use of at least one of the respectivepyrazoline compounds, optionally in form of one of the stereoisomers,preferably enantiomers or diastereomers, a racemate or inform of amixture of at least two of the stereoisomers, preferably enantiomersand/or diastereomers, in any mixing ratio, or a corresponding N-oxidethereof, or a corresponding salt thereof, or a corresponding solvatethereof, and optionally one or more pharmaceutically acceptableexcipients, for the preparation of a medicament for the prophylaxisand/or treatment of food intake disorders, preferably bulimia, anorexia,cachexia, obesity and/or type II diabetus mellitus (non-insulinedependent diabetes mellitus), preferably obesity.

Also particularly preferred is the use of at least one of the respectivepyrazoline compounds, optionally in form of one of the stereoisomers,preferably enantiomers or diastereomers, a racemate or in form of amixture of at least two of the stereoisomers, preferably enantiomersand/or diastereomers, in any mixing ratio, or a corresponding N-oxidethereof, or a corresponding salt thereof, or a corresponding solvatethereof, and optionally one or more pharmaceutically acceptableexcipients, for the preparation of a medicament for the prophylaxisand/or treatment of alcohol abuse and/or alcohol addiction, nicotineabuse and/or nicotine addiction, drug abuse and/or drug addiction and/ormedicament abuse and/or medicament addiction, preferably drug abuseand/or drug addiction.

Medicaments/drugs, which are frequently the subject of misuse includeopioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine,hallucinogens and benzodiazepines.

Also preferred is the use of at least one of the respective pyrazolinecompounds, optionally in form of one of the stereoisomers, preferablyenantiomers or diastereomers, a racemate or in form of a mixture of atleast two of the stereoisomers, preferably enantiomers and/ordiastereomers, in any mixing ratio, or a corresponding N-oxide thereof,or a corresponding salt thereof, or a corresponding solvate thereof, andoptionally one or more pharmaceutically acceptable excipients for thepreparation of a medicament for the prophylaxis and/or treatment of oneor more disorders selected from the group consisting of schizophrenia,anxiety, depression, epilepsy, neurodegenerative disorders, cerebellardisorders, spinocerebellar disorders, cognitive disorders, cranialtrauma, panic attacks, peripheric neuropathy, inflammation, glaucoma,migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer,Raynaud's disease, tremblement disorders, compulsive disorders, seniledementia, thymic disorders, tardive dyskinesia, bipolar disorders,cancer, medicament-induced movement disorders, dystonia, endotoxemicshock, hemorragic shock, hypotension, insomnia, immunologic disorders,sclerotic plaques, vomiting, diarrhea, asthma, memory disorders,prufitus, pain, or for potentiation of the analgesic effect of narcoticand non-narcotic analgesics, or for influencing intestinal transit.

The medicament according to the present invention may be in any formsuitable for the application to humans and/or animals, preferably humansincluding infants, children and adults and can be produced by standardprocedures known to those skilled in the art. The composition of themedicament may vary depending on the route of administration.

The medicament of the present invention may for example be administeredparentally in combination with conventional injectable liquid carriers,such as water or suitable alcohols. Conventional pharmaceuticalexcipients for injection, such as stabilizing agents, solubilizingagents, and buffers, may be included in such injectable compositions.These medicaments may for example be injected intramuscularly,intraperitoneally, or intravenously.

Medicaments according to the present invention may also be formulatedinto orally administrable compositions containing one or morephysiologically compatible carriers or excipients, in solid or liquidform. These compositions may contain conventional ingredients such asbinding agents, fillers, lubricants, and acceptable wetting agents. Thecompositions may take any convenient form, such as tablets, pellets,capsules, lozenges, aqueous or oily solutions, suspensions, emulsions,or dry powdered forms suitable for reconstitution with water or othersuitable liquid medium before use, for immediate or retarded release.

The liquid oral forms for administration may also contain certainadditives such as sweeteners, flavoring, preservatives, and emulsifyingagents. Non-aqueous liquid compositions for oral administration may alsobe formulated, containing edible oils. Such liquid compositions may beconveniently encapsulated in e.g., gelatin capsules in a unit dosageamount.

The compositions of the present invention may also be administeredtopically or via a suppository.

The daily dosage for humans and animals may vary depending on factorsthat have their basis in the respective species or other factors, suchas age, sex, weight or degree of illness and so forth. The daily dosagefor humans may preferably be in the range from 1 to 2000, preferably 1to 1500, more-preferably 1 to 1000 milligrams of active substance to beadministered during one or several intakes per day.

Pharmacological Methods

I. In-vitro Determination of Affinity to CB1/CB2-Receptors

The in-vitro determination of the affinity of the inventive substitutedpyrazoline, compounds to CB₁/CB₂-Receptors is carried out as describedin the publication of Ruth A. Ross, Heather C. Brockie et al.,“Agonist-inverse agonist characterization at CB₁ and CB₂ cannabinoidreceptors of L-759633, L759656 and AM630”, British Journal ofPharmacology, 126, 665-672, (1999), whereby the transfected human CB₁and CB₂ receptors of Receptor Biology, Inc. are used. The radioligandused for both receptors is [³H]-CP55940. The respective parts of thedescription is hereby incorporated by reference and forms part of thepresent disclosure.

II. In-vivo Bioassay System for Determination of Cannabinoic Activity

Mouse Tetrad Model

Substances with affinity for cannabinoid receptors are known to producea wide range of pharmacological effects. It is also known thatintravenous administration of a substance with affinity for cannabinoidreceptors in mice produces analgesia hypothermia, sedation andcatalepsy. Individually, none of these effects can be considered asproof that a tested substance has affinity for cannabinoid-receptors,since all of these effects are common for various classes of centrallyactive agents. However, substances, which show all of these effects,i.e. substances that are active in this so-called tetrad model areconsidered to have affinity for the cannabinoid receptors. It hasfurther been shown that cannabinoid receptor antagonists are highlyeffective in blocking the effects of a cannabinoid agonist in the mousetetrad model.

The tetrad model is described, for example, in the publication of A. C.Howlett et al, International Union of Pharmacology XXVII. Classificationof Cannabinoid Receptors, Pharmacol Rev 54, 161-202, 2002 and David R.Compton et al., “In-vivo Characterization of a Specific CannabinoidReceptor Antagonist (SR141716A) :Inhibition ofTetrahydrocannbinol-induced Responses and Apparent Agonist Activity”, J.Pharmacol. Exp. Ther. 277, 2, 586-594, 1996. The corresponding parts ofthe description are hereby incorporated by reference.

Material and Methods

Male NMRI mice with a weight of 20-30 g (Harlan, Barcelona, Spain) areused in all of the following experiments.

Before testing in the behavioral procedures given below, mice areacclimatized to the experimental setting. Pre-Treatment control valuesare determined for analgesia hot plate latency (in seconds), rectaltemperature, sedation and catalepsy.

In order to determine the agonistic activity of the substance to betested, the mice are injected intravenously with the substance to betested or the vehicle alone. 15 minutes after injection, latency in hotplate analgesia is measured. Rectal temperature, sedation and catalepsyare measured 20 minutes after injection.

In order to determine the antagonistic activity the identical procedureis used as for the determination of the agonistic effects, but with thedifference that the substance to be evaluated for its antagonisticactivity is injectected 5 minutes before the intravenous injection of1.25 mg/kg Win-55,212 a known cannabinoid-receptor agonist.

Hot Plate Analgesia

The hot plate analgesia is determined according to the method describedin Woolfe D. et al. “The evaluation of analgesic action of pethidinehydrochloride (Demerol)”, J. Pharmacol. Exp. Ther. 80, 300-307,1944. Therespective description is hereby incorporated by reference and formspart of the present disclosure.

The mice are placed on a hot plate (Harvard Analgesimeter) at 55±0.5° C.until they show a painful sensation by licking their paws or jumping andthe time for these sensations to occur is recorded. This reading isconsidered the basal value (B). The maximum time limit the mice areallowed to remain on the hot plate in absence of any painful response is40 seconds in order to prevent skin damage. This period is called thecut-off time (PC).

Fifteen minuts after the administration of the substance to be tested,the mice are again placed on the hot plate and the afore describedprocedure is repeated. This period is called the post-treatment reading(PT).

The degree of analgesia is calculated from the formula:% MPE of Analgesia=(PT−B)/(PC−B)×100MPE=Maximum possible effect.Determination of Sedation and Ataxia

Sedation and ataxia is determined according to the method described inDesmet L. K. C. et al. “Anticonvulsive properties of Cinarizine andFlunarizine in Rats and Mice”, Arzneim. -Forsch. (Frug Res) 25, 9, 1975.The respective description is hereby incorporated by reference and formspart of the present disclosure.

The chosen scoring system is

0: no ataxia;

1: doubful;

2: obvious calmness and quiet;

3: pronounced ataxia;

prior to as well as after treatment

The percentage of sedation is determined according to the formula:% of sedation=arithmetic mean/3×100Hypothermia:

Hypothermia is determined according to the method described in David R.Compton et al. “In-vivo Characterization of a Specific CannabinoidReceptor Antagonist (SR141716A) Inhibition ofTetrahydrocannbinol-induced Responses and Apparent Agonist Activity”, J.Pharmacol Exp Ther. 277, 2, 586-594, 1996. The respective description ishereby incorporated by reference and forms part of the presentdisclosure.

The base-line rectal temperatures are determined with a thermometer(Yello Springs Instruments Co., Panlabs) and a thermistor probe insertedto 25 mm before the administration of the substance to be tested. Rectaltemperature is again measured 20 minutes after the administration of thesubstances to be tested. The temperature difference is calculated foreach animal, whereby differences of=−2° C. are considered to representactivity.

Catalepsy;

Catalepsy is determined according to the method described in AlpermannH. G. et al. “Pharmacological effets of Hoe 249: A new potentialantidepressant”, Drugs Dev. Res. 25, 267-282. 1992. The respectivedescription is hereby incorporated by reference and forms part of thepresent disclosure.

The cataleptic effect of the substance to be tested is evaluatedaccording to the duration of catalepsy, whereby the animals are placedhead downwards with their kinlegs upon the top of the wooden block.

The chosen scoring system is:

Catalepsy for:

more than 60 seconds=6; 50-60 seconds=5, 40-50 seconds=4, 30-40seconds=3, 20-30 seconds=2, 5-10 seconds=1, and less than 5 seconds=0.

The percentage of catalepsy is determined according ot the followingformula:% Catalepsy=arithmetic mean/6×100III. In vivo Testing for Antiobesic Activity

The in-vivo testing for antiobesic activity of the inventive pyrazolinecompounds as well as of compounds known from the prior art is carriedout as described in the publication of G. Colombo et al., “AppetiteSuppression and Weight Loss after the Cannabinoid Antagonist SR 141716”;Life Sciences, 63 (8), 113-117, (1998). The respective part of thedescription is hereby incorporated by reference and forms part of thepresent disclosure.

The present invention is illustrated below with the aid of examples.These illustrations are given solely by way of example and do not limitthe general spirit of the present invention.

EXAMPLES Example 1N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamidea) 4-(4-chlorophenyl)-2-oxo-3-butenoic acid

In a three neck flask p-chlorobenzaldehyde (13.3 g, 95 mmoles) and ethylpyruvate (10 g, 86 mmoles) were dissolved in 150 ml of absolute ethanol.The solution was ice cooled to 0° C. and an aqueous solution of NaOH(3.8 g in 45 mL water) was added dropwise keeping the temperature belowor equal to 10° C., whereby a yellow-orange colored precipitate wasformed. The reaction mixture was stirred for 1 hour at 0° C. and anadditional 1.5 hours at room temperature (approximately 25° C.).Afterwards the reaction mixture was cooled down to approximately 5° C.and the insoluble sodium salt of 4-(4-chlorophenyl-2-oxo-3-butenoic acidwas isolated by filtration.

The filtrate was left in the refrigerator overnight, whereby moreprecipitate is formed, which was filtered off, combined with the firstfraction of the salt and washed with diethyl ether. The sodium salt of4-(4-chlorophenyl)-2-oxo-3-butenoic acid was then treated with asolution of 2N HCl, stirred for some minutes and solid4-(4-chlorophenyl)-2-oxo-3-butehoic acid was separated via filtrationand dried to give 12.7 g of the desired product (70% of theoreticalyield).

IR (KBr, cm⁻¹) 3500-2500, 1719.3, 1686.5, 1603.4, 1587.8, 1081.9.

¹H NMR(CDCl₃, δ): 7.4 (d, J=8.4 Hz, 2H), 7.5 (d, J=16.1 Hz, 1H), 7.6 (d,J=8.4 Hz, 2H), 8.1(d, J=16.1 Hz, 1H).

b)5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylicacid

4-(4-chlorophenyl)-2-oxo-3-butenoic acid obtained according to step a)(12.6 g, 60 mmoles), 2,4-dichlorophenylhydrazine hydrochloride (12.8 g,60 mmoles) and glacial acetic acid (200 mL) were mixed under a nitrogenatmosphere and heated to reflux for 4 hours, cooled down to roomtemperature (approximately 25° C.) and given into icewater, whereby asticky mass was obtained, which was extracted with methylene chloride.The combined methylene chloride fractions were washed with water, driedwith sodium sulfate, filtered and evaporated to dryness to give a paleyellow solid (12.7 g, 57% of theoretical yield).

IR (KBr, cm⁻¹): 3200-2200, 1668.4, 1458, 1251.4, 1104.8.

¹H NMR (CDCl₃, δ) 3.3 (dd, 1H), 3.7 (dd, 1H), 5.9 (dd, 1H), 7.09-7.25(m, 7H).

(c)5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylicacid chloride

Under nitrogen atmosphere5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylicacid (2.5 g, 6.8 mmols) obtained according to step (b) was dissolved in4 mL of in thionyl chloride and heated to reflux for 2.5 hours. Theexcess thionyl chloride is removed from the reaction mixture underreduced pressure and the resulting crude residue (2.6 g) is used withoutany further purification.

IR (KBr, cm⁻¹): 1732.3, 1700, 1533.3, 1478.1, 1212.9, 826.6.

d)N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide

Under nitrogen atmosphere N-aminopiperidine (0.6 mL, 5.6 mmoles) andtriethylamine (4 mL) were dissolved in methylene chloride (25 mL). Theresulting mixture was ice-cooled down to 0° C. and a solution of5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylicacid chloride obtained in step (c) in methylene chloride (15 mL) wasadded dropwise. The resulting reaction mixture was stirred at roomtemperature (approximately 25° C.) overnight. Afterwards the reactionmixture was washed with water, followed by a saturated aqueous solutionof sodium bicarbonate, then again with water, dried over sodium sulfate,filtered and evaporated to dryness in a rotavapor. The resulting crudesolid was crystallized from ethanol. The crystallized solid was removedvia filtration and the mother liquors were concentrated to yield asecond fraction of crystallized product. The two fractions were combinedto give a total amount of 1.7 g (57% of theoretical yield) ofN-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamidehaving a melting point of 183-186° C.

IR (KBr, cm⁻¹): 3222.9, 2934.9, 1647.4, 1474.7, 1268.3, 815.6.

¹H NMR (CDCl₃, δ): 1.4 (m, 2H), 1.7 (m, 4H), 2.8 (m, 4H), 3.3 (dd, J=6.1y 18.3 Hz, 1H), 3.7 (dd, J=12.5 and 18.3 Hz, 1H), 5.7 (dd, J=6.1 and12.5 Hz, 1H), 7.0-7.2 (m, 6H), 7.4 (s, 1 H).

The compounds according to the following examples 2-6 have been preparedanalogously to the process described in Example 1.

Example 25-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydra-1H-pyrazole-3-carboxylicacid-[1,2,4]triazol-4-yl amide

Melting point: 134-138° C.

IR (KBr, cm⁻¹): 3448, 1686, 1477, 1243, 1091, 821.

¹H NMR(CDCl₃, δ): 3.1 (dd, J=6.2 and 17.9 Hz, 1H), 3.7 (dd, J=12.3 and17.9 Hz, 1H), 5.9 (dd, J=6.2 and 12.3 Hz, 1H), 7.2-7.5 (m, 7H), 8.7 (s,2H), 12.0 (bs, 1H).

Example 35-(4-Chloro-phenyl)-1-(2,4dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylicacid-(4-methyl-piperazin-1-yl)-amide hydrochloride

Melting point: 150-155° C.

IR (KBr, cm⁻¹): 3433, 1685, 1477, 1296, 1246, 1088, 1014, 825.

¹H NMR (CDCl₃, δ): 2.7 (d, J=4.2 Hz, 3H), 3.0-3.4 (m, 9H), 3.6 (dd,J=11.9 and 17.9 Hz, 1H), 5.8 (dd, J=5.5 and 11.9 Hz, 1H), 7.1 (d, J=8.4Hz, 2H), 7.25 (2d, J=8.4 and 8.7 Hz, 3H), 7.4 (d, J=2.2 Hz, 1H), 7.5 (d,J=8.7 Hz, 1H), 9.8 (s, 1H), 11.2 (bs).

Example 45-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylicacid diethylamide

This compound was obtained in form of an oil.

IR (film, cm⁻¹): 2974, 1621, 1471, 1274, 1092, 820.

¹H NMR (CDCl₃, δ): 1,2 (m, 6H), 3.3-3.9 (m, 6H), 5,6 (dd, J=5.8 and 11.7Hz, 1H), 7-7.25 (m, 7H).

Example 5[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazol-3-yl]-piperidin-1-yl-methanone

Melting point 105-110° C.

IR (KBr, cm⁻¹): 2934, 1622, 1470, 1446, 1266, 1010, 817.

¹H NMR (CDCl₃, δ): 1.7 (m, 6H), 3.4 (dd, J=5.7 and 17.9 Hz, 1H), 3.7 (m,3H), 3.9 (m, 2H), 5.6 (dd, J=6.1 y 11.9 Hz, 1 H), 7-7.25 (m, 7H).

Example 6N-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl]-4-methyl-phenylsulfonamide

This compound was obtained in form of an amorph solid.

IR (KBr, cm⁻¹): 1697, 1481, 1436, 1340, 1169, 1074, 853.

¹H NMR (CDCl₃, δ): 2.4 (s, 3H), 3.2 (dd, J=6.6 and 18.3 Hz, 1H), 3.6(dd, J=12.8 and 18.3 Hz, 1H), 5.8 (dd, J=6.6 and 12.8 Hz, 1H), 7 (d,J=8.2 Hz, 2H), 7.2 (s, 1H), 7.3-7.4 (m, 6H), 8 (d,J=8.1 Hz, 2H), 9(s,1H).

Example 7 N-oxide ofN-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide

Under nitrogen gas as an inert atmosphereN-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide(0.15 g, 332 mmoles) was dissolved in 7 ml of dichloromethane. Theresulting solution was ice-cooled to 0° C. and m-chloroperbenzoic acid(0.204 g, 0.83 mmoles) added in several portions. After stirring for 15minutes a control via thin layer chromatography showed that no startingmaterial was remaining. A saturated solution of sodium bicarbonate wasthen slowly added, the organic phase separated, washed with water, driedover sodium sulfate and filtered. The filtered solution was evaporatedto dryness and the crude product was purified via column chromatographyyielding 78 mg (50% of theoretical yield) of the N-oxide ofN-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamidein form of a white solid having a melting point of 115-120° C.

IR (KBr, cm⁻¹): 3202, 1678, 1654, 1474, 1309, 1107.

¹H-NMR (CDCl₃, δ): 1.6 (m, 2H), 1.8-2.0 (m, 4H), 2.55 (m, 2H), 3.3 (dd,J=6.3 Hz and 18.2 Hz, 1H), 3.7 (m, 3H), 5.8 (dd, J=6.3 Hz and 12.5 Hz, 1H), 7.0-7.3 (m, 7H), 8.5 (s, 1H.)

Pharmacological Data:

I. In-vitro Determination of Affinity to CB₁/CB₂-Receptors

The affinity of the inventive substituted pyrazoline compounds toCB₁/CB₂ receptors was determined as described above. Some of the valuesobtained are given in the following table I: TABLE I CB₁-ReceptorCB₂-Receptor Radiologand: Radiologand: Compound [³H]-CP55940[³H]-CP55940 according to % Inhibition % Inhibition Example 10⁻⁶ MK_(i)(nM) 10⁻⁶ M K_(i)(nM) 1 93% <25 33% >1000 5 79% 111 54% ≈1000As can be seen from the values given in table 1 the inventive pyrazolinecompounds are particularly suitable for regulating the CB₁-Receptor.II. In-vivo Bioassay System for Determination of Cannabinoid Activity

The determinination of cannabinoid activity in-vivo was determined asdescribed above. Some of the values obtained are given in the followingtable II; TABLE II dosis administered 5 mg/kg i.v. Compound dosisadministered: prior to Win 55212-2 in according 5 mg/kg i.v. a dose of1.25 mg/kg i.v. to Agonistic effect Antagonistic Effect example: A B C DA B C D 1 0 0 0 0 74 100 100 100 5 0 50 0 0 50 40 20 20i.v. intravenousA: Hot-Plate testB: HypothermiaC: CatalepsyD: Sedation

As can be seen from the values given in table II the inventivepyrazoline compounds act as cannabinoid receptor antagonists.

III. In-vivo Testing for Antiobesic Activity

The in-vivo testing for antiobesic activity was carried out as describedabove, whereby three different groups of 10 rats each were treated asfollows:

Group I:

Group was treated with vehicle, namely arabic gum (5 wt.-%) in water,

Group II:

The second group of rats was treated with the inventive compoundN-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamideaccording to Example 1. Said compound was administered intraperitoneallyto the rats over a period of 14 days in a daily dosis of (10 mg/kg bodyweight).

Group III:

The third group of rats was treated with Amphetamine, an activeingredient known to reduce appetite. Said compound was administeredintraperitoneally to the rats over a period of 14 days in a daily dosisof (5 mg/kg body weight).

As can be seen from FIG. 1 the body weight is lowered due to theadministration of the inventive compound according to example 1 and thiseffect is also observed after the treatment is ended.

FIG. 2 shows the reduction of food intake due to the administration ofthe inventive compound according to example 1.

1.N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-carboxamide.2. A method for the prophylaxis or treatment of a food intake disordercomprising administering the compound of claim
 1. 3. The method of claim2 wherein the disorder is selected from the group consisting of bulimia,anorexia, cachexia, obesity and type II diabetes mellitus (non-insulindependent diabetes mellitus).
 4. A pharmaceutical composition comprisingthe compound of claim 1.